Trifluoromethionine
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Trifluoromethionine

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Category
Fluorinated amino acids
Catalog number
BAT-008912
CAS number
764-52-3
Molecular Formula
C5H8F3NO2S
Molecular Weight
203.19
Trifluoromethionine
IUPAC Name
(2S)-2-amino-4-(trifluoromethylsulfanyl)butanoic acid
Synonyms
Trifluoro-L-methionine
Density
1.45 g/cm3
Boiling Point
260.6ºC at 760 mmHg
InChI
InChI=1S/C5H8F3NO2S/c6-5(7,8)12-2-1-3(9)4(10)11/h3H,1-2,9H2,(H,10,11)/t3-/m0/s1
InChI Key
YLJLTSVBCXYTQK-VKHMYHEASA-N
Canonical SMILES
C(CSC(F)(F)F)C(C(=O)O)N
1. Trifluoromethionine, a prodrug designed against methionine gamma-lyase-containing pathogens, has efficacy in vitro and in vivo against Trichomonas vaginalis
G H Coombs, J C Mottram Antimicrob Agents Chemother. 2001 Jun;45(6):1743-5. doi: 10.1128/AAC.45.6.1743-1745.2001.
Methionine gamma-lyase, the enzyme which catalyzes the single-step conversion of methionine to alpha-ketobutyrate, ammonia, and methanethiol, is highly active in many anaerobic pathogenic microorganisms but has no counterpart in mammals. This study tested the hypothesis that this pathogen-specific enzyme can be exploited as a drug target by prodrugs that are exclusively activated by it. Trifluoromethionine was confirmed as such a prodrug and shown to be highly toxic in vitro to the anaerobic protozoan parasite Trichomonas vaginalis, to anaerobic bacteria containing methionine gamma-lyase, and to Escherichia coli expressing the trichomonad gene. The compound also has exceptional activity against the parasite growing in vivo, with a single dose preventing lesion formation in five of the six mice challenged. These findings suggest that trifluoromethionine represents a lead compound for a novel class of anti-infective drugs with potential as chemotherapeutic agents against a range of prokaryotic and eukaryotic anaerobic pathogens.
2. Transcriptional and functional analysis of trifluoromethionine resistance in Entamoeba histolytica
Gil M Penuliar, Atsushi Furukawa, Kumiko Nakada-Tsukui, Afzal Husain, Dan Sato, Tomoyoshi Nozaki J Antimicrob Chemother. 2012 Feb;67(2):375-86. doi: 10.1093/jac/dkr484. Epub 2011 Nov 22.
Objectives: Drug resistance in parasitic protozoa is an obstacle to successful chemotherapy. Understanding how pathogens respond to drugs is crucial in preventing resistance. Previously, we have shown that in Entamoeba histolytica, methionine γ-lyase (EhMGL) downregulation results in trifluoromethionine resistance. The transcriptional response, however, of this parasite to the drug is not known. In this study, we used microarray analysis to determine whether additional genes are involved. Methods: The expression profiles of 9230 genes in wild-type and trifluoromethionine-resistant strains were compared. Episomal overexpression of EhBspA1 was performed to verify its role in trifluoromethionine resistance. The transcriptomes of a trifluoromethionine-resistant strain cultured with or without trifluoromethionine, an EhMGL gene-silenced strain, a strain with reduced susceptibility to metronidazole and a wild-type strain under cysteine-deprived conditions were compared to determine the specificity of the changes observed in the trifluoromethionine-resistant strain. Results: The expression of 35 genes differed at least 3-fold between trifluoromethionine-resistant and wild-type strains. Some of the genes play roles in metabolism, the stress response and gene regulation. EhMGL and EhBspA1 were found to be highly downregulated and upregulated, respectively. Overexpression of EhBspA1 conferred partial resistance to trifluoromethionine. Comparative transcriptome analysis showed that genes modulated in trifluoromethionine-resistant strains were specific. Conclusions: E. histolytica has few known resistance mechanisms against drugs. In this study, we showed that aside from EhMGL downregulation, induction of EhBspA1 plays a role in trifluoromethionine resistance. We also showed a unique set of induced genes that could represent the signature profile of trifluoromethionine resistance in E. histolytica.
3. Mechanism of trifluoromethionine resistance in Entamoeba histolytica
Gil M Penuliar, Atsushi Furukawa, Dan Sato, Tomoyoshi Nozaki J Antimicrob Chemother. 2011 Sep;66(9):2045-52. doi: 10.1093/jac/dkr238. Epub 2011 Jun 14.
Objectives: To determine the mechanism of trifluoromethionine resistance in Entamoeba histolytica and evaluate the impact of acquired drug resistance on virulence. Methods: Trifluoromethionine-resistant amoebae were selected in vitro and examined for cross-resistance to antiamoebic drugs, stability of resistance, methionine γ-lyase (MGL) activity, cell adhesion and virulence. Targeted gene silencing was performed to confirm the role of EhMGL. Results: Trophozoites with a resistance index of 154 were obtained. The cells were susceptible to chloroquine, metronidazole, paromomycin and tinidazole, but remained resistant to trifluoromethionine in the absence of drug pressure. A complete lack of EhMGL activity accompanied by increased adhesion and decreased cytolysis were also observed. Silencing of the EhMGL genes resulted in trifluoromethionine resistance. Conclusions: This study provides the first demonstration of trifluoromethionine resistance in a parasitic protozoon. Repression of gene expression of drug targets represents a novel mechanism of resistance in E. histolytica. The information obtained from this work should help further development of trifluoromethionine derivatives that have lower chances of inducing resistance.
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